Terminology for blood group antigens and genes—historical origins and guidelines in the new millennium

In 1901, Landsteiner named the first two blood group antigens A and B, using the first two letters of the al- phabet.1 RBCs not reacting with anti-A and anti-B were called type C.1 In 1902, von Decastello and Sturli2 described RBCs reacting with both anti-A and anti-B but did not give this type a name; they continued calling RBCs that did not react with anti-A and anti-B type C. In a publication in 1910,3 Landsteiner showed serologic results of all four ABO types but did not use the terms O and AB. In 1911, von Dungern and Hirszfeld4 appear to be the first to use the term O to describe RBCs not reacting with anti-A and anti-B and the term AB for RBCs reacting with both anti-A and anti-B. The lack of A and B was indicated by the letter "O", but it is controversial whether this letter should have been printed as a zero (0) or whether the letter O came from the first letter of the German word "ohne" meaning without (i.e., without A or B). The letter O was commonly used in print and speech, and, almost 100 years later, the ISBT Working Party on Terminology for Red Cell Surface Antigens has recommended that we continue to use the letter O.5 Many readers may not realize that there were problems with ABO terminology during the several decades following Landsteiner's discovery. In 1907, Jansky6 proposed using Roman numerals I, II, III, and IV for O, A, B, and AB, respectively. In 1910, Moss7 (in the United States), who had not read Jansky's article, which appeared in an obscure Czech journal, also, independently, suggested using Roman numerals. Unfortunately, Moss suggested IV for group O and I for group AB, a reversal of Jansky's terms. For some years, both numerical terminologies were popular: Moss's nomenclature was popular in the United Kingdom, France, and some parts of the United States, while Jansky's system was popular in other parts of the United States and elsewhere. In 1921, the American Association of Immunology, the Association of Pathologists and Bacteriologists, and the Society of American Bacteriologists made a joint recommendation that, "on the basis of priority,...the Jansky classification be adopted."8(p130) Because of the continuing confusion, Landsteiner suggested in 19279 the universal use of the symbols A, B, O, and AB, instead of Roman numerals. Nevertheless, it is noteworthy that results of a survey published in 192910 indicated that 71 percent of 552 North American hospitals were still using the Moss terminology, 16.5 percent used the Jansky terminology, 2.9 percent used both, and only 4.7 percent used the Landsteiner terminology. Moss's terminology, often combined with letters (e.g., OIV, AII), persisted into the early 1950s in some areas. After the discovery of the Rh system in 1940,11 the nomenclature problem became acute, again because of two different terminologies, the CcDdEe terms of Fisher and Race12 and Race and Sanger13 and the Rh/Hr terms used by Wiener14 and his followers. Thus, in Europe, it was anti-D, -c, -e, etc., and, in most of the United States it was anti-Rho, -hr′, -hr′′, etc. A fascinating review of the history of this controversy has been published.15 A popular way of naming blood group systems was to use all or part of the name of the first antibody maker, or reactive donor (journals such as TRANSFUSION will allow this now only if there is written permission from the patient or donor). For instance, Lewis, Duffy, Scianna, Dombrock, Colton, Gerbich, Cromer, Knops, and Diego were the names of antibody makers. Lutheran should have been Lutteran, which was the name of the donor of the first reactive Lu(a+) RBCs; the original donor blood sample was incorrectly labeled (Tippett P, oral communication, June 1999). Some blood group names came from part of the name or the initials of the antibody maker, such as Kell from Kelleher; JMH from John Milton Hagen; LKE from Luke; Cs from Cost-Sterling; Bg from Bennett-Goodspeed; and Ch and Rg from Chido and Rodgers. On the basis of agreements reached at an international meeting of prominent scientists,16 superscript lower-case letters began to be used to describe new antigens or alleles (e.g., Lea, Fya). Many other examples can be found.17 The derivation of some of the symbols used for the antigens or alleles is interesting. For instance, the Duffy symbol (Fy) came from the last two letters of the antibody maker's name (Duffy), as the first two letters, D and Du, had already been used. The Ok blood group system was named from the family name (Kobutso) of the antibody (anti-Oka) producer; Ko had already been used, so the first letters of the name were reversed to Ok (Morel P, oral communication, June, 1999). Jk came from the initials of the baby (John Kidd) who had hemolytic disease of the newborn, the child of the antibody maker (Mrs. Kidd), as K had already been used for Kell.18 Some of the miscellaneous derivations of names of blood groups are also fascinating. M and N were named with the second and fifth letters of the word immune, because the antibodies were produced by immunizing rabbits with human RBCs, and it was thought that the first letter, I, might be confused with the number 1.19 Although I was not used by Levine and Landsteiner in 1927, it was used, in 1956, by Wiener et al.20 to describe a high-incidence antigen reacting with a powerful cold agglutinin; the letter I was selected to emphasize the high degree of "individuality" of blood specimens failing to react with the patient's serum at room temperature. In 1948, Morgan and Watkins21 suggested changing the terms "anti-O" and "O substance" to "anti-H" and "H substance" ("...the substance might better be called H-substance in place of O-substance, as this would differentiate it as a hetero-genetic, basic or primary substance common to the great majority of red cells irrespective of their ABO group."). The name of another high-incidence antigen (U) was derived from "the almost universal distribution of the new blood factor."22(p1445) Sid (Sda) was the first name of the Head of Maintenance of the Lister Institute in London, whose RBCs were part of an in-house panel and reacted strongly with antibodies that were eventually named anti-Sda (Tippett P, oral communication, June, 1999). The Indian blood group system was named because of its association with antibody producers from India. A similar rationale was used for the Bombay (Oh) blood group, the first examples of which were found in that city in India. The name for the S antigen/antibody came from the city (Sydney) where the first anti-S was discovered (Sanger R, oral communication, June 1999). Xg and XK were named because of their association with the X chromosome; the g in Xg stood for Grand Rapids (Michigan), the site of the discovery, and the K in XK for its more obvious association with the Kell system. Because the first example of En(a–) RBCs reacted like enzyme-treated RBCs, Darnborough et al. suggested that they "may have abnormal red cell envelope structure (hence the choice of the symbol En), which may be due to some enzyme abnormality."23(p253) A low-incidence determinant on Rh:33 RBCs with depressed C and/or e was named FPTT, because three of the four propositi worked for the French Post and Telegraphic Telecommunications.24 A partial D phenotype associated with FPTT was named DFR, "because F is a mnemonic for FPTT, and since a minimum of three letters is required for synonyms, R was added to F to reflect the initial French connection."25(p616) A few blood groups were named after the scientists who discovered them. For instance, the Landsteiner-Wiener (LW) system was so named because the original Rh antibody, produced by Landsteiner and Wiener by injecting rabbits and guinea pigs with RBCs from rhesus monkeys, and named Rh (anti-Rho or anti-D) after rhesus monkey, was later found to be different from human Rh antibodies (i.e., anti-D). The original antibody produced in rabbits and guinea pigs was found to be identical to human antibodies (anti-LW) that reacted with almost all RBCs tested, but that reacted much better with D+ than D– RBCs; this antibody was named anti-LW after Landsteiner and Wiener. T was named after Oluf Thomsen of Copenhagen, who, in 1926, called the new antigen "L" (for Latency). L was later termed T, in honor of Thomsen, by his assistant Friedenreich, who showed the relationship of T to bacterial infection.26 The "n" of Tn came from the French word "nouvelle," for a new T antigen.27 Pr came from protease-sensitive.28 The superscript "T" of IT was used because maximal amounts of the antigen were thought to be present during transition from i to I.29 In 1961 and 1962, Allen and Rosenfield30 and Rosenfield et al.31 suggested a numerical nomenclature for the Kell and Rh systems. The numerical nomenclature was intended to allow investigators to report serologic findings without necessarily including genetic interpretations (D or Rho became Rh1, C or rh′ became Rh2, etc., and D+c+e– became Rh:1,4, –5, etc.). Rosenfield et al.31 allocated Rh1 to Rh25, and other investigators have since allocated Rh26 to Rh52.17,32 The numerical terminology was extended to other systems, (e.g., Lutheran); new antigens were named with numbers instead of the traditional names of antibody makers. Thus, the traditional/conventional/popular terminology for antigens is a mixture of letters (e.g., Lea, Fya, K) and numbers (e.g., Rh29, Lu3, K11), with a few remaining names (e.g., Evans, Crawford).17,32 In 1980, the ISBT set up a Working Party on Terminology for Red Cell Surface Antigens. It should be emphasized that their mandate was to devise a uniform nomenclature that would be both eye- and machine-readable. Their first report, in 1982, stated, "The ISBT Working Party is not trying to change the nomenclature of the blood groups. Numbers assigned to specificities are proposed as standard alternatives to current alphabetical names in those circumstances where numbers are necessary as in some computer systems."33(p165) The working party suggested using upper-case letters and Arabic numbers for system and antigen codes. New antigens named after the introduction of the terminology use three to six upper-case letters (BOW, JONES, etc.). Each system, collection, or series of antigens is given a number (e.g., ABO system = 001) and each antigen within the system is given a number (e.g., A = 001, B = 002). Thus, in computer code, A is 001001 and B is 001002. Sinistral zeros may be omitted so that A can be expressed as 1.1 and B as 1.2. In the Rh system (004), D = 001, C = 002, E = 003, etc. Thus, for the computer, D, C, and E are 004001, 004002, and 004003, respectively. The system symbol and the antigen number, minus the sinistral zeros, may be used (e.g., RH1, RH2, RH3, respectively). Table 1 shows some of the alternatives. The full report of the ISBT Working Party terms appears elsewhere.5,34,35 Although all terms in Table 1 are acceptable, TRANSFUSION chooses to use traditional terminology in most cases. In 1984 and 1992, Issitt and Crookston36 and Issitt and Moulds37 published in TRANSFUSION advice regarding terminology. These articles provided a basis for the terminology used by TRANSFUSION. In addition, the articles gave advice on the correct use of the English language in connection with immunohematologic terms; examples of common errors were given. This advice is still pertinent and has been reemphasized by Issitt and Anstee in the first chapter of their recently published textbook.17 Table 2 shows acceptable terms for blood group systems and antigens. The headings are the system names. Under each system are listed the antigens. Traditional terms are given first; ISBT terms are given in parentheses.Table 3 shows the ISBT collections of antigens. Once more, TRANSFUSION prefers to use traditional names (e.g., I and i rather than I1 and I2). Tables 4 and 5 show low- and high-incidence antigens by name and/or symbol. TRANSFUSION will usually use the symbol when describing these low- and high-incidence antigens. Table 6 shows RBC antigens that are described in the literature and have traditional names but no ISBT names or symbols. In print, the symbol for a gene or gene cluster is usually italicized (or underlined if italics are not possible). The traditional,17,32 ISBT,5,34,35 or International System for Gene Nomenclature (ISGN)38–40 blood group symbols can be used (e.g., Fy, FY, or DARC, respectively; Jk, JK, or SLC14A1, respectively). Table 7 shows the terminology for blood group genes that has been suggested (e.g., by ISBT) on the basis of serologic findings and that used by the Human Gene Mapping (HGM) Nomenclature Committee (which formulated the ISGN), which relates to known functional aspects of the gene product. For instance, the ISGN uses FUT3 (fucosyl transferase 3) for Le, DARC (Duffy antigen receptor for chemokine) for Fy, SLC14A1 (solute carrier family 14, urea transporter member 1) for Jk, SLC4A1 (solute carrier family 4, anion exchanger member 1) for Di, ACHE (acetylcholinesterase) for Yt, AQP1 (aquaporin) for Co, FUT1 (fuco-syltransferase 1) for H, GYPC (glycophorin C) for Ge, DAF (decay-accelerating factor) for Cromer, CR1 (complement receptor 1) for Kn, CD44 for In, and CD147 for Ok. Such functional terms will continually be changing. For instance, the ISBT gene symbol for the Diego (DI) blood group system has not changed for years, but the ISGN name has changed from DI to EPB3 (erythrocyte surface protein band 3) to AE1 (anion exchanger 1) to the present SLC4A1 (solute carrier family 4, anion exchanger member 1). Although it may be difficult to remember two nomenclatures, there is merit in maintaining each system. For serologists, the ISBT designations are a reminder of the evolution of blood group science and the well-characterized RBC antigens that are still determined today. For molecular biologists, the ISGN designations provide clues to the character or function of a gene product. As the list of gene designations is growing at a rapid pace, investigators should contact the HGM Nomenclature Committee before naming any gene (the names and contact information for the appropriate HGM Nomenclature Committee members are provided in White et al.40). Finally, it is important for investigators to realize that ISGN gene designations change as more functional information becomes available. TRANSFUSION will continue to use traditional gene terminology (e.g., Rh, Fy, Jk), but, when investigations are molecular in nature, the ISGN symbols will sometimes be used in addition, in parentheses (e.g., Fy [DARC], Jk [SLC14A1]). Antigens of three blood group systems (Chido/Rodgers, Rh, and MNS) are encoded by two homologous genes that are adjacent on the same chromosome. Because of this, the genes and gene products of these systems can include hybrids. For the Chido/Rodgers blood group system, the two common gene names and the encoded products are listed (Table 7). In the Rh system, both the ISBT and the ISGN have adopted the terms RHD and RHCE to describe the genes that encode production of the D antigen-bearing and the C- or c- plus E- or e-bearing proteins, respectively. When the gene involved is not known (e.g., in the description of an Rh antigen not yet characterized at the molecular level) the term RH can be used. For the MNS system, the ISBT gene name of MNS is used for both the genes and the two products (GPA and GPB): GPA carries the M/N polymorphism and GPB carries the S/s polymorphism. The ISGN names both genes (i.e., GYPA encodes GPA and GYPB encodes GPB). A third gene in this family (GYPE) has not been shown conclusively to encode its product (GPE) in the RBC membrane. The products of each gene listed in Table 7 refer to all polymorphic forms, the number of which ranges from 1 antigen (P, Hh, Ok, Raph systems) to nearly 50 antigens (Rh system). Alleles are alternative forms of a particular gene. Thus, they are expressed by using the gene name and an appendage that indicates the particular allele. For alleles, the ISGN uses the gene name, followed by an asterisk and a letter or number in italics (e.g., RH*D, KEL*2, DARC*A).39 A space instead of an asterisk is also sometimes used.38 Unfortunately, ISBT uses numbers (e.g., LU*1) where ISGN uses letters (e.g., LU*A). Table 8 gives some examples of the three terminologies currently used. Table 9 shows the terminology for serologic phenotypes (traditional and ISBT). DNA is made up of bases, the sugar 2-deoxyribose, and phosphate groups. The bases are of two classes, pyrimidine and purine. DNA is a helical polymer of deoxyribose linked by phosphate groups; one of its four bases projects from each sugar molecule of the sugar–phosphate chain. A base sugar is a nucleoside. A base sugar–phosphate unit is a nucleotide. Table 10 shows the one-letter abbreviations used. When bps are quantified, the terms kilo-bp (kbp) and 1 million bp (Mbp) are sometimes used (e.g., a 235-bp repeat sequence; a 47-kbp vector genome; 1 Mbp of DNA). Sometimes the length of nucleotide molecules is qualified by using the suffix mer (e.g., 20mer = 20 nucleotides). A codon is a sequence of three nucleotides in a DNA molecule that codes for an amino acid or biosynthetic message. Codons are also referred to as nucleotide triplets (e.g., CAT, ATC, ATT). Sequences of repeating nucleotides, also known as tandem repeats, are indicated in parentheses with n equaling the number of repeats (e.g., [TTAGGG]n, [GT]n). The phosphates that join the DNA nucleotides link the of one deoxyribose to the of the For of the is to show the at the and the at the The of DNA have the from the to the while its appears it with the on the of 20 amino Each amino acid is encoded by one or more in DNA (e.g., and for Table the symbols for the amino A nomenclature for gene has recently been and this is the terminology that TRANSFUSION will This nomenclature for the common types of nucleotide and amino acid is described using examples from blood group examples are listed in Table The A of the codon is any (e.g., alternative a sequence from a or an alternative should be for The nucleotide number is listed the change (e.g., or is given. in gene is a C at in the by an A in allele. by numbers followed by the Thus, the polymorphism is the of a at of the ABO gene. For of more than one the is for a can be is followed by and the For one of the phenotype is the of a T and of the AQP1 gene. In the of in the of in repeats, the is (e.g., of a C into the sequence would be as an the C and the sequence as the first of the first repeat followed by the repeat sequence (in and the number of repeats (e.g., an sequence at and 4 and in the the full sequence is this can be used for As this sequence is often not the sequence numbers can be used, with numbers with the of the donor site and numbers from the of the site The base can be by the number (e.g., or by the number with a (i.e., the number of the last of the the or the number of the first of the following that For one that to the phenotype is can also be as is the first of 7 of This can be or a For Table is letter amino acid is X for a the three letter is also The amino acid is listed followed by the codon number and the This nomenclature the meaning of C, A, and T as amino or The amino acid of the protein is given followed by the amino acid number, and the amino For the polymorphism is of codon for that is and correct terminology is as important as using correct English in and The correct for both is the most of the Unfortunately, investigators and are not to correct blood group antigen nomenclature and terminology. that this review of current nomenclature will readers and other realize that nomenclature of the history of RBC antigen discovery, indicates functional for RBC proteins, and for on RBC surface antigens. by which 20 are used for may be by a of a and to may a or polymorphism in the gene. or at which DNA is A molecule of DNA has by which of DNA a DNA of an to of the A set of three that for one amino acid or DNA that expressed of the by the of of DNA are within and Such are most common in expressed that and in functional gene such as and of and of by which the bps are to two and of the of a read from to or from to of at the of an and of to acid to a of a gene that is It is present only in or The or to the of the and the of the A DNA that to phenotype or In the of a gene may be characterized by or Gene of genetic information as a of in the of the are so that one as the which is made to the second the donor (i.e., base on one the of the and DNA a of the the length of the that the sequence of the donor results in while due to a high degree of results in Gene of genetic (i.e., using a as the The of an that and DNA (i.e., DNA). A series of linked alleles within a on a or chromosome. of DNA from a of may sequence or The of may be used to and of genes often for genes that early show high of of in which the enzyme used for the (i.e., is added to DNA that has been to The of acid or polymorphic of DNA are found the and are not The of DNA are of the gene at the and are not expressed as part of the gene product of tandem repeats, usually 1 to 4 bp in DNA is into which is eventually into or that has in the sequence of a gene or genetic are several of and in which by length by are and to or are used to the or of acid In a the is In a the is of the of the that are not of DNA are found at the and the often termed are also found within genes (e.g., and and A nucleotide without a phosphate of DNA and of phosphate a sugar molecule in deoxyribose in and are of two 1) to or pyrimidine to and to pyrimidine and pyrimidine to purine. may of may also polymer of made in for use as of DNA that may be read the same in the and for on one DNA and on the may a structure that In for the of a sequence of using The of the is such that in A of such as have been used to DNA into DNA that is found in number is and the acid that to The of the for of the and DNA are in A labeled that to produced by the of a or that is into an appropriate vector system (i.e., For may be produced by the of the gene into an that may be into cells which to the production of the or that and of For to may or The or to the of the and the of the by which (i.e., is to is length polymorphism by the of DNA with a particular are on the and of which may from one to the because of or in DNA is not but with to of in and S is a of the for the of expressed The by of as the are used to the of and of in the and DNA is by the in which may be in of high and or because the association of DNA by of the DNA of DNA or of is a of the of to that are made in of DNA that to that a structure and protein The to an and with and of an amino acid to the of the is by the the of a read from to or from to number of tandem Alleles may because of in the number of tandem polymorphism is by DNA with for a length to the number of A repeat unit is 5 to bp in genetic that, when into a DNA can of the DNA into a A gene as it in

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